Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Mechanisms of Impaired HIV-associated B cell and Pneumococcal Vaccine responses

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HIV-associated B cell defects are associated with an increased incidence of secondary infections, autoimmune disease and B cell lymphomas. High rates of infection, such as pneumococcal pneumonia and bacteremia, and poor responses to preventive vaccines among persons with HIV infection, even with antiretroviral therapy, may be related to an impaired ability of B cells to generate antibodies of sufficient quantity, quality and function to control these pathogens. The development of effective antibodies requires mutations in the antigen-binding hypervariable region to enhance binding to pathogens as well as changes in the conserved constant regions (switch from IgM to IgG or IgA) to enhance killing of organisms. Both of these effects are controlled by a pivotal molecule, activation-induced cytidine deaminase (AID), in B cells in inductive sites in lymphoid tissue, the germinal centers (GC). HIV infection can have dramatic detrimental effects on the architecture and function of germinal centers as well as on B cells themselves. The consequence is the production of antibodies in low concentrations and with limited protective activity. We propose to study B cell abnormalities in patients with HIV infection and control adults by characterizing B cell phenotype by multiparameter flow cytometry, expression, regulation and function of AID to support B cells in response to model stimuli in vitro as well as with in vivo challenge with pneumococcal vaccines. We utilize clinical, cellular and molecular approaches to understanding B cell defects during HIV infections and vaccines in the context of evaluating the potential protection afforded by the antibodies they elicit as well as in their role as controlled and targeted probes of integrated immune function.
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